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Page 6 of 15 Kaya et al. Neuroimmunol Neuroinflammation 2019;6:5 I http://dx.doi.org/10.20517/2347-8659.2018.70

certain neurodegenerative conditions, MAPK and PI3K/AKT signaling pathways provide a crucial function
in neuronal survival [10,23,64] . In one in vivo study, researchers performed facial nerve axotomy on rats to create
a peripheral nerve injury model. They then analyzed the ERK/MAPK and PI3K/AKT pathways by evaluating
[10]
the phopshorylation levels of ERK and AKT in axotomized neurons . Seven days after the nerve axotomy,
ERK and AKT phosphorylation levels were shown to have increased, while the rate of apoptosis was shown
to have decreased. These researchers also used the MAPK inhibitor or PI3K/AKT phosphorylation inhibitor
to determine survival rate of facial neurons, regenerated axon number and length of regenerated axons, in
the event that ERK/MAPK and PI3K/AKT signaling cascades were silenced. When ERK phosphorylation
was inhibited, only the regenerated axon length was obviously decreased. However, inhibition of AKT
phosphorylation significantly reduced not only the length of regenerated axons but also the number of
new axons and the survival rate of neurons. Results of this study clearly indicate that nerve injury through
[10]
axotomy activated both PI3K/AKT and ERK/MAPK signaling in neurons, implying an effort to survive .
In another in vitro study investigating the function of ERK/MAPK and PI3K/AKT pathways in neuronal
survival after injury, researchers demonstrated that ciliary neurotrophic factor (CNTF) promotes survival
and process outgrowth via ERK/MAPK and PI3K/AKT pathways in oxytocinergic neurons of hypothalamic
[64]
organotypic cultures .
Finally, a research group performed an in vitro study to analyze the role of MAPK signaling in preventing
[23]
cytosine arabinoside (araC)-induced apoptosis in sympathetic neurons . They induced apoptosis with
araC and used the selective MAPK inhibitor PD98059 to test whether MAPK inhibition affected the rate
of apoptosis. Their results showed that MAPK inhibition increased the rate of araC-induced apoptosis in
the presence of nerve growth factor (NGF) in a p53-dependent manner. This finding indicated that the
MAPK signaling pathway plays a critical role in protecting primary neurons against apoptosis under certain
[23]
pathological conditions .
The aforementioned studies dealing with neurons and astrocytes demonstrate the controllable nature
of ERK/MAPK and PI3K/AKT pathways through different effector molecules, including p53, NGF,
CNTF and, most probably, Speedy/RINGO. This implies that properly balancing the activity of these
pathways with respect to different neuropathological conditions and different cell types may help prevent
neurodegeneration and apoptosis.

2+
To recapitulate, deregulation of intraneuronal Ca influx - which is one of the well-known triggering events
of secondary injury in SCI - results in activation of calpain. This activation subsequently increases p53 levels,
which abnormally regulate MAPK and PI3K/AKT pathways and lead to severe neurodegeneration and
apoptotic death. A number of investigations have studied whether the reduction of apoptotic effects of Ca
2+
influx can prevent or minimize secondary injury in SCI.

Estrogen is one inhibitor that has been used to protect cells in culture and in rat models against apoptosis.
[65]
Researchers showed that estrogen and its analogs decreased the activity of calpain protease and inhibited
[66]
[67]
apoptosis in microglia, neurons and oligodendrocytes .
Melatonin, known for its antioxidant and anti-inflammatory properties, is another anti-apoptotic agent
in SCI. It has been shown that melatonin promotes neuronal survival by preventing secondary injury
2+
through free oxygen radical scavenging [57,58] . Melatonin also works to alleviate intracellular Ca influx and
subsequent calpain activation [65-70] .

2+
Abnormal intracellular Ca influx, as an integral part of SCI, has apoptotic effects such as aberrant
regulation of MAPK and AKT signaling pathways via p53 induction. Because of this, it is vital to overcome,
2+
or at least minimize, this apoptotic effect of Ca and provide neuroprotection to neurons at the injury